Role of metalloproteinases in mammary gland remodeling

金属蛋白酶在乳腺重塑中的作用

• 批准号: 7911061
• 负责人: MINA BISSELL
• 金额: $ 9.98万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7911061
• 关键词: Address; Adenocarcinoma; Affect; Apoptosis; Behavior; Biochemistry; Biological; Biological Assay; Biological Process; Breast; Cancer Etiology; Cell Culture Techniques; Cell physiology; Cells; Cellular biology; Cessation of life; Development; Differentiation and Growth; Disease; Ductal; Ductal Epithelial Cell; Dysplasia; Environment; Epithelial; Epithelial Cells; Epithelial-Stromal Communication; Epithelium; Equilibrium; Extracellular Matrix; Extracellular Matrix Degradation; Functional disorder; Funding; Genes; Genomic Instability; Goals; Growth; Growth Factor; Hyperplasia; Lead; Lesion; Life; Lupus erythematosus cell; MMP3 gene; Malignant Neoplasms; Mammary Neoplasms; Mammary gland; Matrix Metalloproteinase Inhibitor; Matrix Metalloproteinases; Mechanics; Mediator of activation protein; Mesenchymal; Metalloproteases; Methods; Modeling; Molecular; Morphogenesis; Mus; Mutate; Myoepithelial cell; Neoplasms; Normal tissue morphology; Pathogenesis; Pathologic; Pathologic Processes; Pathway interactions; Phenotype; Play; Premalignant; Process; Research; Role; Series; Signal Pathway; Signal Transduction; Stem cells; Stromal Cells; Stromelysin 1; Structure-Activity Relationship; System; Testing; Therapeutic Intervention; Tissue Inhibitor of Metalloproteinase-1; Tissues; Transgenic Organisms; Transplantation; Trees; Woman; Women' s Health; base; cell behavior; cellular imaging; epithelial to mesenchymal transition; genetic manipulation; human MMP14 protein; in vivo; in vivo Model; inhibitor/antagonist; insight; intercellular communication; malignant breast neoplasm; mammary epithelium; mammary gland development; mutant; neoplastic; neoplastic cell; novel; overexpression; public health relevance; reconstitution; research study; response; tumor; tumor progression

DESCRIPTION (provided by applicant): The global objective of this research is to elucidate the molecular mechanisms underlying tissue remodeling during growth, differentiation and development in mouse mammary gland, and to gain insights into how this process goes awry in pathologic disorders, including cancer. A central issue in achieving this goal is to understand how the stromal microenvironment regulates the invasive behavior of normal epithelia during pubertal development and how mammary luminal and myoepithelial cells interact to form a stable ductal tree. Extracellular matrix (ECM)-degrading matrix metalloproteinases (MMPs) are expressed in the stroma. They play a role in normal tissue remodeling during development and also contribute to the pathogenesis of tumor progression. The present proposal addresses the mechanisms by which these stromal MMPs orchestrate the cross talk between mesenchymal and epithelial compartments. The goal for this proposal is to dissect, in molecular and cell biological detail, how MMPs affect branching morphogenesis through their ability to orchestrate the stromal microenvironment of the breast. The project will use a toolbox of genetically modified mice and mammary cells, organotypic cell culture models and in vivo transplantation systems to interrogate these models and determine the critical substrates of MMPs, what signaling pathways are regulated by MMPs and how intercellular communication is affected by MMPs. The organotypic cultures will be analyzed for growth, morphogenesis, differentiation, and invasive behavior using a combination of live cell imaging, biochemistry and cell biology. In vivo analysis will utilize genetically modified mammary glands and orthotopic transplants of mammary epithelial cells transduced with wild type and mutated MMPs, their inhibitors and substrates. The role of MMPs in fine-tuning intercellular communication during branching morphogenesis will be studied with emphasize on myoepithelial cells. The study will focus on candidate substrates in the Wnt pathway for MMP3/stromelysin, and how their cleavage by MMPs affects signaling in the mammary epithelium. By dissecting how these signaling pathways operate in balancing stem cell activation, proliferation and differentiation and the mechanical environment in the pubertal mammary gland, the applications to breast cancer should continue to unfold. These experiments will give insights into how misregulation of MMPs directly leads to the development of breast cancer. An understanding of how MMPs function in the normal tissue and how disruption of their function promotes neoplasia is necessary to achieve the long-term goal of finding cures for breast cancer. PUBLIC HEALTH RELEVANCE: Breast cancer is the second leading cause of cancer deaths in women and is the most common cancer among women. This study addresses an important aspect of women's health, of how matrix metalloproteinases regulate normal and neoplastic mammary gland function. The approaches used in this project will elucidate how MMPs alter the structural microenvironment, and how this influences the critical responses of growth and invasion in normal and abnormal mammary gland epithelium and stroma. These studies may form the basis of intervention and therapy in breast cancer, potentially in the premalignant lesions.

描述（由申请人提供）：这项研究的总体目标是阐明小鼠乳腺生长、分化和发育过程中组织重塑的分子机制，并深入了解这一过程在包括癌症在内的病理性疾病中如何出错。实现这一目标的一个核心问题是了解基质微环境如何调节青春期发育期间正常上皮细胞的侵袭行为，以及乳腺管腔和肌上皮细胞如何相互作用形成稳定的导管树。细胞外基质 (ECM) 降解基质金属蛋白酶 (MMP) 在基质中表达。它们在发育过程中的正常组织重塑中发挥作用，也有助于肿瘤进展的发病机制。本提案阐述了这些基质 MMP 协调间充质和上皮区室之间串扰的机制。该提案的目标是从分子和细胞生物学细节中剖析 MMP 如何通过其协调乳房基质微环境的能力来影响分支形态发生。该项目将使用转基因小鼠和乳腺细胞、器官型细胞培养模型和体内移植系统的工具箱来研究这些模型并确定 MMP 的关键底物、MMP 调节哪些信号通路以及 MMP 如何影响细胞间通讯。将结合活细胞成像、生物化学和细胞生物学对器官型培养物的生长、形态发生、分化和侵袭行为进行分析。体内分析将利用转基因乳腺和用野生型和突变型 MMP、其抑制剂和底物转导的乳腺上皮细胞的原位移植。将重点研究肌上皮细胞，研究 MMP 在分支形态发生过程中微调细胞间通讯的作用。该研究将重点关注 MMP3/基质溶解素 Wnt 通路中的候选底物，以及 MMP 对其的裂解如何影响乳腺上皮中的信号传导。通过剖析这些信号通路如何平衡干细胞激活、增殖和分化以及青春期乳腺的机械环境，乳腺癌的应用应该会继续展开。这些实验将深入了解 MMP 的失调如何直接导致乳腺癌的发展。了解 MMP 如何在正常组织中发挥作用以及其功能的破坏如何促进肿瘤形成对于实现寻找乳腺癌治疗方法的长期目标是必要的。公共卫生相关性：乳腺癌是女性癌症死亡的第二大原因，也是女性中最常见的癌症。这项研究涉及女性健康的一个重要方面，即基质金属蛋白酶如何调节正常和肿瘤性乳腺功能。该项目中使用的方法将阐明 MMP 如何改变结构微环境，以及这如何影响正常和异常乳腺上皮和间质的生长和侵袭的关键反应。这些研究可能构成乳腺癌（可能是癌前病变）干预和治疗的基础。